The study objective is to determine the safety and efficacy of long term ceftriaxone treatment in subjects with amyotrophic lateral sclerosis (ALS), a uniformly progressive, untreatable, and fatal neurodegenerative disorder. In an attempt to widen the search for potential therapeutic agents, a National Institute of Neurological Disorders and Stroke (NINDS) led cooperative group performed an in-vitro screening program of 1040 FDA approved drugs in 29 assays relevant to various neurodegenerative disorders. Several cephalosporins, including ceftriaxone showed hits in ALS relevant assays. Efficacy was noted in models screening for compounds that increased expression of the astrocytic glutamate transporter, EAAT2, and in models of superoxide dismutase mediated toxicity. Ceftriaxone, a third generation cephalosporin with good CNS penetration and a long half-life, also has antioxidant properties and can rescue motor neurons in culture from chronic glutamate toxicity. Because neither the safety of long term ceftriaxone administration nor the extent of its penetration to the cerebrospinal fluid (CSF) are fully characterized, we propose a novel study design to expedite drug development while ensuring safety. The placebo-controlled clinical trial will enroll 600 research participants with ALS using a three-step sequential drug development design. We will determine optimal dosage, safety and efficacy of ceftriaxone in ALS. Our goals are to determine the steady state levels and population kinetics of ceftriaxone in the CSF (Aim 1, STAGE 1), define the safety and tolerability of ceftriaxone after a minimum of 16 weeks of daily treatment (Aim 2, STAGE 2), and to ascertain whether chronic treatment with ceftriaxone prolongs survival in ALS (Aim 3, STAGE 3). In STAGE 1, 60 subjects at eight centers will be enrolled in a pharmacokinetic study. Subjects will receive placebo, 2 or 4 grams ceftriaxone daily. After 7 days they will be admitted to the hospital for a plasma and CSF pharmacokinetic study. All 60 subjects will continue treatment and enter STAGE 2 to determine safety and tolerability after 16 weeks of daily treatment. STAGE 1 results will be used to modify the STAGE 2 design. Based on data from both STAGES 1 and 2, an assessment will be made as to whether a dose producing sufficient CSF levels to generate a biological effect can be tolerated by ALS patients. If the decision is affirmative, the study will be expanded to 600 randomized research participants at 40 centers in US and Canada. Subjects in the STAGE 1 and 2 studies will roll-over into the larger phase. Patients will remain in study until 52 weeks after the last patient is enrolled. The primary outcome measure for the STAGE III study will be time to death, tracheostomy or permanent assisted ventilation. Secondary outcome measures will include ALSFRS-R, vital capacity, strength, and the long-term safety and tolerability of ceftriaxone in this population.